The invention relates to novel benzoxazoles which are employed in the pharmaceutical industry for the preparation of medicaments.
1. Known Technical Background
International Patent Application WO 96/11917 describes substituted benzoxazoles as cyclic nucleotide phosphodiesterase inhibitors of type 4. U.S. Pat. No. 4,405,633 and European Patent Application EP-A-127 066 propose substituted benzoxazoles as agents for the prevention and treatment of asthma.
2. Description of the Invention
It has now been found that the benzoxazoles described below in greater detail, which differ from the previously published compounds by a different type of substitution, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I 
in which
R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,
R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or 1-4C-alkoxy-1-4C-alkyl,
R3 is hydrogen, hydroxyl, nitro, cyano, ethynyl, carboxyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
A is B, xe2x80x94CH(R4)xe2x80x94,  greater than Cxe2x95x90O or  greater than Cxe2x95x90Nxe2x80x94R5, where
B is oxygen (xe2x80x94Oxe2x80x94), imino (xe2x80x94NHxe2x80x94), sulfinyl (xe2x80x94S(O)xe2x80x94), sulfonyl (xe2x80x94S(O)2xe2x80x94) or carbonylimino (xe2x80x94C(O)NHxe2x80x94) and
R4 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, hydroxyaminocarbonyl (xe2x80x94C(O)NHOH) or 1-4C-alkoxyaminocarbonyl,
R5 is hydroxyl or 1-4C-alkylcarbonyloxy,
and the salts of these compounds.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpenty), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-6C-Alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Alkoxy radicals having 1 to 6 carbon atoms which may be mentioned are, for example, the hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyioxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexyl-methoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
Completely or predominantly fluorine-substituted 1-4C-alkoxy which may be mentioned are, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and the 1,2,2-trifluoroethoxy radicals, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radicals.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. The 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may preferably be mentioned.
1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl and the methoxyetnyl radicals and the butoxyethyl radical.
1-4C-Alkoxycarbonyl represents a carbonyl group to which is bonded one of the abovementioned 1C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl (CH3Oxe2x80x94C(O)xe2x80x94) and the ethoxycarbonyl (CH3CH2Oxe2x80x94C(O)xe2x80x94) radicals.
In addition to the carbonyl group, mono- or di-14C-alkylaminocarbonyl radicals contain one of the abovementioned mono- or di-14C-alkylamino radicals. Examples which may be mentioned are the N-methyl, the N,N-dimethyl, the N-ethyl, the N-propyl, the N,N-diethyl and the N-isopropylaminocarbonyl radicals.
A 1-4C-alkylaminocarbonyl radical which may be mentioned is, for example, the methoxyaminocarbonyl radical (xe2x80x94C(O)NHOCH3).
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which is bonded one of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetoxy radical (CH3C(O)xe2x80x94Oxe2x80x94).
Suitable salts of compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases are also suitable. Examples of salts which bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts which can initially be obtained as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and also their salts, when they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I to be emphasized are those in which
R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,
R2 is 1-4C-alkyl, 3-5C-cycloalkyl, 3-5C-cycloalkylmethyl or 1-2C-alkoxy-1-2C-alkyl,
R3 is hydroxyl, cyano, carboxyl, 1-2C-alkoxy or 1-2C-alkoxycarbonyl,
A is B, xe2x80x94CH(R4)xe2x80x94,  greater than Cxe2x95x90O or  greater than Cxe2x95x90Nxe2x80x94R5, where
B is oxygen (xe2x80x94Oxe2x80x94), sulfinyl (xe2x80x94S(O)xe2x80x94), sulfonyl (xe2x80x94S(O)2xe2x80x94) or carbonylimino (xe2x80x94C(O)NHxe2x80x94) and
R4 is hydroxyl, carboxyl, 14C-alkoxycarbonyl or aminocarbonyl,
R5 is hydroxyl or 1-4C-alkylcarbonyloxy,
and the salts of these compounds.
Compounds of the formula I particularly to be emphasized are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkyl or 3-5C-cycloalkyl,
R3 is hydroxyl, cyano or methoxy,
A is B, xe2x80x94CH(R4)xe2x80x94 or  greater than Cxe2x95x90O, where
B is oxygen (xe2x80x94Oxe2x80x94) or sulfonyl (xe2x80x94S(O)2xe2x80x94),
R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
One embodiment of the particularly preferred compounds of the formula I are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkyl or 3-5C-cycloalkyl,
R3 is hydroxyl, cyano or methoxy,
A is B or xe2x80x94CH(R4)xe2x80x94, where
B is oxygen (xe2x80x94Oxe2x80x94) or sulfonyl (xe2x80x94S(O)2xe2x80x94),
R4 is carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is 1-4C-alkoxy,
R2 is 1-4C-alkyl,
R3 is cyano,
A is B, xe2x80x94CH(R4)xe2x80x94 or  greater than Cxe2x95x90O, where
B is oxygen (xe2x80x94Oxe2x80x94) and
R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
Particularly preferred compounds of the formula I are those in which
R1 is methoxy,
R2 is methyl or isopropyl,
R3 is cyano,
A is B, xe2x80x94CH(R4)xe2x80x94 or  greater than Cxe2x95x90O,
B is oxygen (xe2x80x94Oxe2x80x94) and
R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,
and the salts of these compounds.
One embodiment of the particularly preferred compounds of the formula I are those in which
R1 is methoxy,
R2 is methyl or isopropyl,
R3 is cyano,
A is oxygen (xe2x80x94Oxe2x80x94),
and the salts of these compounds.
The compounds of the formula I can be presentxe2x80x94if A is xe2x80x94CH(R4)xe2x80x94 as cis or trans isomers. The invention therefore includes both all pure cis and trans isomers and their mixtures in any mixing ratio. The pure cis isomers are preferred in this connection.
The invention further relates to processes for the preparation of the compounds of the formula I and their salts.
Compounds of the formula I in which A is xe2x80x94CH(R4)xe2x80x94, R1, R2 and R3 have the meanings indicated above and R4 is carboxyl can be prepared, for example, by hydrolyzing corresponding compounds of the formula I in which, is xe2x80x94CH(R4)xe2x80x94 and R4 is alkoxycarbonyl and, if desired, then converting compounds of the formula I obtained into their salts, or converting salts of the compounds of the formula I obtained into the free compounds.
If desired, further compounds of the formula I can be converted into other compounds of the formula I by derivatization (in particular of the radicals R3 and R4) in a manner known to the person skilled in the art. In this manner, for example, compounds of the formula I in which R1, R2 and R3 have the meanings indicated above, A is xe2x80x94CH(R4)xe2x80x94 and R4 is aminocarbonyl, mono- or di-alkylaminocarbonyl, alkoxyaminocarbonyl or hydroxyaminocarbonyl, are also accessible.
The hydrolysis of compounds of the formula I in which A is xe2x80x94CH(R4)xe2x80x94 and R4 is alkoxycarbonyl is carried out by application of methods known to the person skilled in the art.
Compounds of the formula I in which A is xe2x80x94CH(R4)xe2x80x94, R1, R2 and R3 have the meanings indicated above and R4 is alkoxycarbonyl are obtained, for example, by solvolysis of corresponding compounds of the formula I, in which A is 
The solvolysis is preferentially carried out in an absolute alcohol as a solvent under acidic conditions in the presence of a mercury salt, such as, for example, mercury(II) chloride.
Compounds of the formula I, in which A is 
and R1, R2 and R3 have the meanings indicated above, can be prepared, for example, from the corresponding compounds of the formula II 
by reaction with 2-lithium-2-trimethylsilyl-1,3-dithiane.
The reaction is expediently carried out at low temperatures (preferably xe2x88x9260xc2x0 to xe2x88x92100xc2x0 C.) under a protective gas atmosphere in an inert solvent such as, for example, n-hexane, diethyl ether or tetrahydrofuran or mixtures thereof.
Compounds of the formula II in which R1 and R2 have the abovementioned meanings and R3 is cyano can be prepared, for example, by application of known methods starting from corresponding compounds of the formula III 
in which X is the group xe2x80x94CH2CN, according to reaction scheme 1. 
The compounds of the formula III in which R1 and R2 have the meanings indicated above and X is the group xe2x80x94CH2CN can be prepared according to the general reaction scheme 2. 
The synthesis of compounds of the formula III is described by way of example under xe2x80x9cstarting compoundsxe2x80x9d. Further compounds can be prepared analogously.
The preparation of compounds of the formula V is described, for example, by M. Grossa, F. Wessely in Monatshefte Chemie 1966, 97, 1384-1390.
Compounds of the formula I in which R1 and R2 have the abovementioned meanings, R3 is hydrogen or cyano and A is xe2x80x94CH(OH)xe2x80x94 can be prepared from corresponding compounds of the formula II by selective reduction of the carbonyl group.
The preparation of the keto compounds of the formula II in which R3 is cyano or hydrogen is described in reaction schemes 1 and 3. 
Compounds of the formula II in which R1 and R2 have the abovementioned meanings and R3 is hydrogen are accessible, for example, by addition of appropriate compounds of the formula III, in which X has the meaning lithium, to 1,4-cyclohexanedione, subsequent elimination of water and selective reduction of the resulting double bond. The 1,4-cyclohexanedione is expediently employed in partially protected form, for example as a monoethylene ketal, and the protective group is removed again after reaction has taken place (reaction scheme 3).
Compounds of the formula III in which X is lithium are accessible from corresponding compounds of the formula III in which X is halogen, in particular bromine, by metal-halogen exchange.
The reduction of the carbonyl group in compounds of the formula II is carried out in a manner known to the person skilled in the art, preferably in suitable inert solvents such as 1,2-dimethoxyethane or an alcohol such as methanol, using a suitable reductant such as, for example, sodium borohydride or lithium borohydride.
Compounds of the formula I in which R1 and R2 have the abovementioned meanings, R3 is cyano, nitro or 1-4C-alkoxycarbonyl and A is oxygen (xe2x80x94Oxe2x80x94), imino (xe2x80x94NHxe2x80x94), sulfinyl (xe2x80x94S(O)xe2x80x94) or sulfonyl (xe2x80x94S(O)2xe2x80x94) can be prepared, for example, from compounds of the formula III in which R1 and R2 have the meanings indicated above and X is xe2x80x94CH2CN, xe2x80x94CH2NO2 or xe2x80x94CH2COOR (Rxe2x95x901-4C-alkyl) by reaction with suitably activated ethers, amines, sulfines or sulfones.
An The reactions are preferably carried out in anhydrous inert solvents such as, for example, THF, DMF, DMSO or HMPT or mixtures thereof and, depending on reactivity of the reagents employed, at temperatures between xe2x88x9230xc2x0 C. and 100xc2x0 C.
After deprotonation of the xe2x80x94CH2CN, xe2x80x94CH2NO2 or the xe2x80x94CH2COOR (Rxe2x95x901-4C-alkyl) group by a suitable base, ring formation is carried out by reaction with an ether, amine, sulfine or sulfone provided with suitable leaving groups. Suitable leaving groups which may be mentioned are halogen, in particular chlorine and bromine, and reactive esterified hydroxyl groups (e.g. the toluenesulfonyloxy group).
Suitably activated ethers (1), amines (2), sulfines (3) and sulfones (4) which suggest themselves are, for example, bis[2-(toluene-4-sulfonyloxy)ethyl]ether (1), N-benzyl-bis[2-(toluene-4-sulfonyloxy)-ethyl]amine (2), bis[2-(toluene-4-sulfonyloxy)ethyl]sulfine (3) and bis(2-chloroethyl) sulfone (4), (1) can be prepared according to C. Almensa, A. Moyano, F. Serratosa, Tetrahedron 1992, 48, 1497-1506, (2) or (3) can be prepared from the corresponding bis-hydroxyl compounds, N-benzyl-bis(2-hydroxyethyl)-amine (Mamaew, Schischkin, J. Org. Chem. (USSR), engl. Transl. 1966, 2, 584) or bis(2-hydroxyethyl) sulfine (Price, Bullit, J. Org. Chem. 1947, 12, 277) by ditosylation.
The protective group of the amine (2) temporarily introduced can be removed again after ring formation has taken place. Bis(2-chloroethyl) sulfone (4) is commercially obtainable.
Compounds of the formula III in which R1 and R2 have the meanings indicated above and X is xe2x80x94CH2COOR can be prepared, for example, by hydrolysis and subsequent esterification of the corresponding compounds of the formula III in which X is xe2x80x94CH2CN.
The preparation of compounds of the formula III in which X is xe2x80x94CH2NO2 is described, for example, in J. Organic Chemistry, 1988, 53, 2872-2873.
Compounds of the formula I in which R1 and R2 have the meanings indicated above, R3 is 1-4C-alkoxy and A is oxygen (xe2x80x94Oxe2x80x94) can be obtained from the corresponding compounds of the formula I in which R3 is hydroxyl by reaction with suitable alkylating agents.
Compounds of the formula I in which R1 and R2 have the meanings indicated above, R3 is hydroxyl and A is oxygen (xe2x80x94Oxe2x80x94) can be obtained, for example, from compounds of the formula III in which R1 and R2 have the meanings indicated above and X is lithium by reaction with tetrahydropyran-4-one.
Compounds of the formula I in which R1, R2 and R3 have the meanings indicated above, A is  greater than Cxe2x95x90Nxe2x80x94R5 and R5 is hydroxyl can be obtained by reaction of the corresponding compounds of the formula II with hydroxylamine.
By means of further derivatizations of these oxime compounds known to the person skilled in the art on the basis of his/her expert knowledge, those compounds of the formula I in which A is carbonylimino (by Beckmann rearrangement of the corresponding oxime compounds) or in which A is  greater than Cxe2x95x90Nxe2x80x94R5 and R5 is 1-4C-alkylcarbonyloxy (by acylation of the corresponding oxime compounds) are also accessible.
It is known to the person skilled in the art that it can be necessary in the case of a number of reactive centers on a starting or intermediate compound to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description of the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is then added.
The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this manner, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.